The majority of peptide like thrombin inhibitors that have been reported in the literature contain a basic group in the so called P1-position (R. Pfau, “Structure-based design of thrombin inhibitors”, Current Opinion in Drug Discovery & Development, 6, 437-450, 2003). Examples of such basic groups include the basic amino acids arginine and lysine, and also guanidines and benzamidines. The basic moiety in these compounds is considered to be essential for antithrombotic activity. However, such highly basic groups are generally protonated at physiological pH and as a consequence such compounds are poorly absorbed across the gastrointestinal tract after oral dosing and have low oral bioavailability.
Therapeutic agents that may be given orally are, in general, greatly preferred and have enhanced commercial potential because of their inherent ease of use.
In the International Patent Application WO 98/47876 (Akzo Nobel N. V.) a class of thrombin inhibitors is disclosed having an aminoisoquinoline moiety as a basic group and these compounds have improved transepithelial transport properties. In particular this patent application exemplifies the compounds N-(carboxymethyl)-D-phenylalanyl-[(1-amino-6-isoquinolinyl)methyl]-L-prolinamide (WO98/47876: example 77) and N-(carboxymethyl)-D-(4-methoxyphenyl)alanyl-[(1-amino-6-isoquinolinyl)methyl]-L-prolinamide (WO98/47876: example 111as), as well as prodrug ester derivatives thereof.
It is desirable to develop more highly available thrombin inhibitors, particularly those suitable for oral administration.